Genomics, Sidedness Guide Treatment Selection in Metastatic CRC

Zev A. Wainberg, MD

Next-generation sequencing (NGS) is replacing single-gene testing for patients with metastatic colorectal cancer (mCRC), explained Zev A. Wainberg, MD, and Jaffer A. Ajani, MD, who added that when this information is coupled with tumor sidedness, it can inform the use of targeted therapy, doublet chemotherapy plus an EGFR antibody, and triplet chemotherapy regimens.

“We’re moving away from a la carte testing to getting a full NGS panel on everybody, and for community oncologists, it tends to be harder to do that sometimes. But I do see more and more referrals coming in already having had a full NGS panel, even in first-line metastatic colon cancer. As the cost goes down and the accessibility increases, we suspect those trends will increase,” said Wainberg.

In an interview with OncLive®, Wainberg and Ajani discussed the increasing incidence of CRC diagnoses in younger patients, the significance of studying genomics and actionable targets that can be tested for to help guide treatment decisions for patients with newly diagnosed disease, and the rationale for conducting full NGS panels on patients.

Wainberg is an associate professor of medicine and surgery in the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), co-director of the UCLA Gastrointestinal Oncology Program, and director of the Early Phase Clinical Research Program at the Jonsson Comprehensive Cancer Center. Ajani serves as professor of medicine and internist in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center,

Moreover, Ajani and Wainberg discussed how to best utilize information provided to inform treatment decisions, treatment approaches for patients with newly diagnosed RAS wild-type mCRC, and factors that affect influence selecting a 2- vs 3-drug chemotherapy regimen.

OncLive®: Could you discuss some of the latest trends, survival, demographics, and epidemiology of mCRC?

Ajani: CRC remains a significant problem globally. There are almost 1.8 million new cases and 700,000 deaths each year. Since 1990, the incidence in people younger than 50 years has been rising almost 2%. Several thousand deaths were recorded in 2020 in that age group, and we don’t know what is going on there. There’s some suspicion that younger people are more sedentary than they used to be and that processed food and obesity may be responsible, but it’s a real mystery and very alarming situation. Overall, the incidence of CRC has gone down. Some of the early detection strategies have worked, but it’s still hard to motivate individuals. I’m hoping that as we go forward liquid biopsy will provide a better opportunity for early detection.

Wainberg: It’s been interesting that we see the population steadily decrease. We’re seeing more and more younger people under the age of 45 years, particularly in rectal cancer, and even in circumstances where presumably these are active people who eat well, we still see this unusual epidemiologic trend, which is very alarming. It’s good to see the screening societies take notice because they changed the recommendation earlier this year to allow for screening colonoscopies in anybody over 45 years old, down from 50 previously. It is a big deal when a screening society changes its recommendations.

Are there any notable genomic differences between younger and older patients with mCRC?

Wainberg: There have been several studies published on the genomic differences. As far as I can tell, it’s not clear that they represent a distinct genomic subgroup that is altogether too different from your otherwise older patients who develop mCRC. However, I know there a lot of studies and efforts looking at that.

Ajani: It’s going to be a big challenge for younger investigators to figure this out. It will have to be multiple types of interrogations to get a handle on this. And even if you figure it out, it’s going to be hard to motivate younger people to use an early detection strategy. At least checking for a KRAS mutation in the blood, or maybe a combination of 2 or 3 biomarkers, may be able to help us.

Wainberg: It’s going to be a multipronged approach trying to figure out why this phenomenon is occurring. As it relates to treatment, usually our tendency is to think that the younger patients can handle the more intense therapies, and that’s often true. However, we’re learning now that many patients who are well into their 70s can handle intense combination chemotherapies as well.

Age isn’t the only factor, of course. But Dr Ajani, if we talk about molecular testing in colon cancer, it’s a little different than gastric cancer, I suppose, since it is a whole different panel that is usually sent. Besides looking for KRAS and RAS status, is there anything else you regard as critical?

Ajani: The NCCN [National Comprehensive Cancer Network] also has recommended HER2 testing, microsatellite instability [MSI] status, BRAF, and NRAS is creeping in. One that is not included right now is the liquid biopsy, which probably will become routine as we go forward, especially if the platform gets larger. But colon cancer is ahead of other GI [gastrointestinal] tumors in a larger panel of biomarkers that are becoming rather standard and actionable.

Wainberg: Most institutions, and I’m sure your institution and ours, have a large internal panel, which includes MSS [microsatellite stability] status, KRAS, NRAS, and BRAF. And now, I totally agree with you, just like in gastric cancer, we now see HER2 make its way into the NCCN guidelines. Even with several HER2-directed agents showing activity, particularly in RAS wild-type tumors with both novel agents, such as [fam-trastuzumab deruxtecan-nxki (Enhertu)], but also combination therapies—pertuzumab [Perjeta] and trastuzumab [Herceptin], trastuzumab and tucatinib [Tukysa], you name it—there is some element of encouraging response rate here. I do tend to check HER2 as well in every patient, particularly those who are KRAS wild-type.

Should every patient with newly diagnosed mCRC undergo NGS?

Wainberg: Regarding NGS, everybody has a different preferred panel. A lot of times when I have a patient who has a KRAS mutation, I find the full NGS panel [does] not give the kind of high yield information I would otherwise like. But there are some rare fusions, whether it’s NTRK or whether it’s the rarer patients who we’re only going to pick up on through NGS. In your institution, do they routinely send for a full NGS panel even after documentation of a RAS mutation?

Ajani: This is not routine. It’s being done more and more, and our NGS panel is expanding. That doesn’t mean it’s going to be more helpful, but you’ll at least get more information. It is being done more commonly because, especially when you do primary surgery, you’ve got a lot of tumor tissue that you can process. That doesn’t mean it’s totally representative of the metastatic disease, but you get a lot of information from the primary [tumor].

Wainberg: It’s particularly true in young patients, where even if the data don’t necessarily suggest a distinct molecular phenotype, there is the tendency to want to look for every rarest of mutations that may be of relevance down the road.

Ajani: Also, the germline Lynch syndrome, particularly, is important in CRC, MSI-high patients, and so on.

Wainberg: Yes, and I do think that in many GI cancers now, we’re learning that, also with very limited costs, it’s worth doing a multicancer genetic panel in CRC, where Lynch syndrome is relatively easy to diagnose nowadays. But for patients who are young, we should be testing for a more hereditary gene panel. I had a patient not long ago with colon cancer who had a BRCA mutation, and it was only picked up with a limited family history of cancer. Colon cancer is not one of the first ones you think about when you think about BRCA, but certainly this patient had one, and there is an increased incidence in BRCA carriers, albeit smaller of CRC. There’s little downside to doing these things nowadays.

With this information, how do you approach selecting systemic therapy?

Wainberg: Dr Ajani, if we have a patient with newly diagnosed disease who has RAS/RAF wild-type status, in your center, how is it determined? Should the patient go on standard doublet chemotherapy with a monoclonal antibody? Or a triplet chemotherapy, which tends to be FOLFOXIRI [folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan] vs the addition of cetuximab [Erbitux] or not?

Ajani: For KRAS wild-type patients, cetuximab or panitumumab [Vectibix] with chemotherapy is going to be useful, especially if it is a left-sided [tumor]. But I think it’s individual preference; there’s no hard and fast rule. I’ll mention this review article that Deborah Schrag, [MD, MPH,] wrote in JAMA [Journal of the American Medical Association]; it’s a beautifully written paper, where she addresses this kind of issue. But it’s not a fixed recommendation. There are some studies showing that cetuximab or EGFR inhibition in KRAS wild-type patients could be beneficial. It doesn’t prevent you from using antiangiogenic agents later.

Wainberg: I agree. The field has undergone a lot of changes in the past few years, and one of them is trying to optimize which patients get EGFR antibodies up front. These left-sided KRAS wild-type tumors, which are themselves very discrete from right-sided tumors and their phenotype, are the patients in whom these drugs should be used. We’re learning more and more that in right-sided patients, there’s probably limited benefit to EGFR inhibitors, even in RAS wild-type disease. This is mostly retrospective, but it seems to be very consistent across any of the larger FIRE-3 trials or CALGB 80405 trials, but even more contemporary trials with panitumumab as well. Left-sided RAS wild-type tumors are the best bang for your buck of these drugs and almost should be reserved for those patients. When we do see patients with newly diagnosed metastatic colon cancer, we tend to think about that right away, as opposed to waiting for the second or third line, perhaps, like we used to reserve for EGFR antibodies. Some people nowadays regard the response rate as so high that they would even be utilized in patients who are ultimately going to go to the operating room, although that’s been controversial with the neoadjuvant use of EGFR antibodies.

When should you select 3 chemotherapy drugs vs 2 chemotherapy drugs?

Wainberg: In colon cancer, a lot of people have also started to like FOLFOXIRI because there have been more and more randomized data sets and even meta-analyses now showing survival advantages of FOLFOXIRI over, in most of the cases FOLFIRI [folinic acid, 5-fluorouracil, irinotecan] as the control arm because those studies were done in Italy. The consistency is there, interestingly, and it’s not clear in which subgroups or not, but it is there. I tend to still use it in younger patients who I feel confident can handle the neutropenia and bone marrow suppression that is going to be induced with 3 cytotoxics, and in patients who need an immediate response, because there your response rate is upward of 70%.

For patients who have big bulky primary rectal tumors, or big bulky primary tumors with large bulky liver metastatic disease, I tend to like FOLFOXIRI as an up-front regimen. There are even smaller studies combining EGFR inhibitors with FOLFOXIRI, nonrandomized to my knowledge, but they show extraordinarily high response rates in that select group. But if I have a patient with a big bulky tumor, and especially on the younger side, I tend to use FOLFOXIRI right away, and I feel increasingly comfortable with that decision, with the more data that come out.

If there’s potentially resectable liver metastasis, such as a borderline situation, would you use a triplet?

Wainberg: Yes, but not for too long, we don’t want to introduce CASH [chemotherapy-associated steatohepatitis] or any other issues into the liver. We would probably think about a 3-month course. But yes, if the expectation is that you need that nice response, there’s good evidence that approach works. Also, I saw published recently in JCO [Journal of Clinical Oncology], was the…experience with locally advanced rectal cancer, where they randomized patients to the classical chemotherapy [and] radiation, but they used FOLFIRINOX [folinic acid, 5-fluorouracil, irinotecan, oxaliplatin] in France. They showed a very high response rate for locally advanced rectal cancer with a TNT [total neoadjuvant therapy] strategy. The point being that in that disease there are very high response rates with 3-drug regimens.

With EGFR antibodies, here too we’re going to increase response rate in our left-sided wild-type tumors. In someone who’s maybe not as big and bulky, you’re still getting a higher response rate than you are with chemotherapy.